CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Methods: AI438048 was a Phase 1, open-label, single-sequence study performed in 18 healthy subjects, who received a single dose (SD) of rosuvastatin 10mg on Day 1 (Treatment A) followed by a 3-day washout, BMS-663068 600mg twice daily (BID) on Days 5–8 (Treatment B), rosuvastatin 10mg SD + BMS-663068 600mg BID on Day 9, and BMS-663068 600mg BID on Days 10–12 (Treatment C). Serial blood samples were collected for 96 hours post-dose on Days 1 and 9. Plasma concentrations were quantified by validated LC/MS/ MS methods. Geometric mean ratios and 90% confidence intervals were derived for rosuvastatin PK parameters using linear mixed-effects models. Adverse events (AEs) were monitored throughout the study. Results: After coadministration with BMS-663068, rosuvastatin peak (C max ) and total (AUC[INF]) exposures increased by 78% and 69%, respectively, vs exposures observed with rosuvastatin alone (Table). Rosuvastatin terminal plasma half-life and time of peak exposure were unaffected by BMS-663068 coadministration. All treatments were generally well tolerated, with no deaths, serious AEs or discontinuations due to AEs. Overall, 6 subjects (33.3%) reported ≥1 AE, which were all mild to moderate, and the majority had resolved by study end. Conclusions: BMS-663068 coadministration increased rosuvastatin exposure vs rosuvastatin administered alone (C max and AUC[INF] increased by 78% and 69%, respectively). Multiple BMS-663068 doses were generally well tolerated when coadministered with rosuvastatin 10mg. In vitro and clinical data suggest that BMS-663068 can be coadministered with statins that are substrates of OATP or BCRP, but dose adjustment of certain statins may be required.

461LB Early Evidence of Antiviral Activity and Safety of ABX464 in HIV Treatment-Naïve Patients Didier Scherrer 1 ; Jean-Marc Steens 2 ; Supparatpinyo Kuanchai 3 ; RatanasuwanWinai 4 ; Kiat Ruxrungtham 5 ; Regine Rouzier 6 ; JamalTazi 7 ; Paul Gineste 8 ; Hartmut Ehrlich 8 ; Robert Murphy 9 1 ABIVAX, Montpellier, France; 2 ABIVAX, Paris, France; 3 Rsr Inst for Hlth Sciences, Chiang Mai Univ, Chiang Mai, Thailand; 4 Siriraj Hosp, Bangkok, Thailand; 5 HIV-NAT, Thai Red Cross AIDS Rsr Cntr, Bangkok, Thailand; 6 Cap Rsr, Phoenix, Mauritius; 7 Univ of Montpellier, Montpellier, France; 8 ABIVAX SA, Paris, France; 9 Northwestern Univ, Feinberg Sch of Med, Chicago, IL, USA Background: ABX464 is a first-in-class antiviral drug candidate for the treatment of patients with HIV-infection. It is an orally available small molecule that blocks HIV replication through an entirely novel mechanism, inhibition of Rev activity. Preclinical data in humanized mice showed that ABX 464 monotherapy had an antiviral effect which was sustained after treatment interruption ( Campos et al, Retrovirology 2015 12:30 ) A prior food-effect study demonstrated a 3-fold increase in parent drug exposure when administered with food without a significant impact on the active glucuronide metabolite. Methods: The objective of this study was to evaluate the safety of ABX-464 at ascending doses versus placebo in HIV-infected treatment-naive patients. Patients were randomized into successive cohorts of 8 patients where 6 received 14-or 21 days of ABX 464 and 2 placebo. Patients fromMauritius and Thailand were included in the study after confirmation of HIV infection and no history of prior antiretroviral therapy. At day 0, patients received the first dose of ABX-464/ placebo in a once daily schedule. Safety assessments and laboratory parameters were recorded throughout the study. After completion of each cohort, a DSMB reviewed safety data and recommended whether the next cohort be initiated at a higher dose. Successive cohorts received 25, 50, 75, 100 and 150 mg QD. The 25, 50 and 100 mg.cohorts took drug fasting for 21 days, the 75 and 150 mg cohorts took drug with food for 14 days. Results: Safety and Tolerability : The main adverse events noted were nausea, vomiting and headache. All adverse events were grade 1 or 2 and all patients completed at least 14 days of treatment. Viral load reduction > 0.5 log was observed in 1/6 patients in the 75 mg cohort, 2/6 patients in the 100 mg cohort and 4/6 patients in the 150 mg cohort; there were no significant viral load changes in the 6 placebo patients from these cohorts. Conclusions: ABX 464 was well tolerated in this first study in HIV infected patients. ABX 464 monotherapy showed early antiviral activity in HIV-infected treatment naïve patients. These results warrant the further planned development of this novel acting antiretroviral drug. 462 A Quantitative Model of ART Efficacy Explains the Clinical Success of Dolutegravir Sarah B. Laskey 1 ; Robert Siliciano 2 1 Johns Hopkins Univ, Baltimore, MD, USA; 2 Howard Hughes Med Inst, Baltimore, MD, USA Background: The clinical success of antiretroviral drug combinations is highly correlated with the results of in vitro drug efficacy assays, except in the case of regimens containing first-generation integrase strand transfer inhibitors (InSTIs). The second-generation InSTI dolutegravir (DTG) has enjoyed enormous clinical success in the two years since its FDA approval, but its pharmacodynamic properties in combination with other antiretroviral drugs and against HIV-1 containing InSTI resistance mutations have not been thoroughly evaluated by quantitative in vitro models. Methods: We used an in vitro infectivity assay to quantify the efficacy of DTG in combination with nucleoside analog reverse transcriptase inhibitor (NRTI) pairs abacavir/lamivude (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC). We compared empirical measurements of antiretroviral activity to the Bliss Independence and Loewe Additivity models of combined drug efficacy to calculate the degree of independence for the interactions between DTG and each NRTI or NRTI pair. From these results, we calculated the instantaneous inhibitory potential (IIP) of DTG-containing regimens at clinical concentrations. We also measured pharmacodynamic properties of DTG against HIV-1 containing InSTI resistance mutations. Results: The combined efficacies of DTG and NRTIs follow the model of Bliss Independence for every combination tested except for DTG/TDF, which demonstrates synergy. The combination DTG/ABC/3TC follows the model of Bliss Independence, while DTG/TDF/FTC demonstrates synergy. Importantly, both three-drug combinations have average clinical IIP values of >6.5; at clinical concentrations, DTG-containing regimens reduce the number of productive infection events per dosing interval by an average of >6.5 logs.

Poster Abstracts

178

CROI 2016